This invention relates to the treatment of an allergic condition using substituted pyrazoles.
Atopic allergies afflict at least 20% of populations in developed countries and comprise a wide range of IgE-mediated diseases such as hay fever, asthma, atopic dermatitis, and food allergies. Exposure of an allergic subject to relevant allergens cross-links allergen specific IgE bound to mast cells, triggering degranulation and release of proinflammatory mediators, such as histamine and eicosanoids, which cause the weal-and-flare response on a skin test. Characteristically, this early response is followed by a prolonged late reaction in which inflammatory cells, particularly eosinophils and activated TH-2 CD4 T cells, are recruited to the site of allergen exposure. Inflammatory cytokines such as IL-4 and IL-5, both produced by TH-2 cells, are important for IgE production by B cells and for eosinophilia, respectively. Immunotherapies targeting CD4 T cells have been shown to be effective in reducing the production of IgE, the activation of proinflammatory cells, and the release of inflammatory mediators.
Current allergy therapies targeting CD4 T cells have met with mixed success. Desensitization with allergen extracts or vaccines is effective for many allergens, such as the Hymenoptera insect sting which can induce life-threatening allergic reactions. The mechanism may be either induction of T cell tolerance or the conversion of TH-2 to TH-1. However, such treatment requires a long-term treatment regime, frequent doctor visits and prior stabilization by other medications, and is associated with a certain morbidity rate and rare deaths. Alternatively, immunosuppressive drugs such as steroids which effectively stabilize ongoing allergy responses, are often associated with severe side effects.
The activation of CD4 T cells is a major factor in the initiation and maintenance of the allergic response. Allergens are taken up by specialized antigen presenting cells (APCs) such as dendritic cells and B cells. Protein allergens pass through the endosomal or lysosomal system where they are degraded by different proteases. These peptide fragments are bound by the MHC class II molecules which, at the cell surface, are heterotrimeric complexes consisting of two transmembrane glycoprotein chains (xcex1 and xcex2) that form a binding scaffold for the third component, a peptide of 11-20 amino acids. The antigen-MHC class II molecule complex is recognized by CD4 T cells and leads to the activation of the T cell. Activated T cells in turn activate several other components of the immune system, such as B cells and macrophages, that are crucial for the body""s response to pathogens, but also lead to the symptoms of allergies.
Class II molecules, like other transmembrane proteins, are translocated into the endoplasmic reticulum (ER) after synthesis, where they associate with a third protein, the invariant chain (Ii). The invariant chain molecule is a type II transmembrane protein that serves as a class II-specific chaperone, promoting the exit of class II-Ii complexes from the ER and preventing class II molecules from binding to peptides and unfolded proteins in the ER and in the secretory pathway. A targeting motif in the cytoplasmic tail of Ii directs the class II-Ii complexes from the secretory pathway into the endosomal system.
Before the MHC class II molecules can present antigen the Ii must be removed by a series of proteases that break down Ii. The resultant Ii peptide fragments, called class II-associated invariant chain peptides (CLIP), occupy the peptide binding groove of the class II molecule, and in most cases are not spontaneously released. The CLIP protects the class II binding pocket from collapsing both during intracellular transport and after Ii degradation in the endosomal system. Binding of antigenic peptides generated from endocytosed proteins requires an empty, and yet open binding site. The CLIP therefore must be released while the open binding site is stabilized to allow the binding of other peptides. Human Leukocyte Antigen-DM (xe2x80x98HLA-DMxe2x80x99) mediates both of these functions, thus promoting the binding of antigenic peptides. After acquiring peptides, the class II molecules are transported to the cell surface via routes that are largely unknown.
In view of the above, inhibition of invariant chain proteolysis will prevent removal of Ii from the class II binding pocket, which in turn will specifically block antigen binding to the MHC class II molecule.
Cathepsin S (xe2x80x98CatSxe2x80x99) is a cysteine protease expressed in lymphatic tissues. CatS mediates invariant chain proteolysis, which is a prerequisite for peptide loading of MHC class II molecules (Riese et al. (1996) Immunity 4:357). CatS has 50-60% homology with cathepsins L and K, but differs from them in that it has a broad pH optimum that extends to alkaline pH. CatS modulates antigen presentation in animal models, and inhibitors are effective in an asthma model (Riese et al. (1998) J. Clin. Invest. 101:2351). Mice deficient in cathepsin S have an impaired ability to present exogenous proteins by professional antigen presenting cells (Nakagawa et al. (1999) Immunity 10:207; Shi et al. (1999) Immunity 10:197).
Compounds that inhibit the proteolytic activity of human cathepsin S are expected to find utility in the treatment of chronic autoimmune diseases including, but not limited to, lupus and rheumatoid arthritis; and have potential utility in modulating the immune response to tissue transplantation. Methods of modulating autoimmunity with an agent that modulates cathepsin S activity, e.g., proteolysis of the Ii chain, as well as methods of treating a subject having an autoimmune disorder, methods of evaluating a treatment for its ability to modulate an immune response are described in WO 99/58153.
Compounds somewhat similar to those of the present invention are described in the following references.
Winters, et. al. (Winters, G.; Sala, A.; Barone, D.; Baldoli, E. J. Med. Chem. 1985, 28, 934-940; Singh, P.; Sharma, R. C. Quant. Struct-Act. Relat. 1990, 9, 29-32; Winters, G.; Sala, A.; Barone, D. in U.S. Pat. No. 4,500,525 (1985)) have described bicyclic pyrazoles of the type shown below. R never contains a heterocyclic ring and no protease inhibitor activity is ascribed to these molecules; they are described as xcex11-adrenergic receptor modulators. 
Shutske, et. al. claim the bicylic pyrazoles below. The pyridine ring is aromatic in their system (Shutske, G. M.; Kapples, K. J.; Tomer, J. D. U.S. Pat. No. 5,264,576 (1993)). Although reference is made to R being a linker to a heterocycle, the claims specify only R=hydrogen. The compounds are referred to as serotonin reuptake inhibitors. 
The compound 2-[4-[4-(3-methyl-5-phenyl-1H-pyrazol-1-yl)butyl]-1-piperazinyl]-pyrimidine is known from EP-382637, which describes pyrimidines having anxiolytic properties. This compound and analogs are further described in EP-502786 as cardiovascular and central nervous system agents. Pharmaceutical formulations with such compounds are disclosed in EP-655248 for use in the treatment of gastric secreation and anti-ulcer agents. WO-9721439 describes medicaments with such compounds for treating obsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesis and motion sickness.
The compounds 5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole and 5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole, in particular the hydrochloride salts thereof, are known from WO-9853940 and CA 122:314528, where these and similar compounds are described as kinase inhibitors in the former reference and possessing affinity for benzodiazepine receptors in the latter reference.
The present invention features the use of cathepsin S inhibitors to treat allergic conditions, including but not limited to atopic allergies. Examples of an allergic condition include hay fever, asthma, atopic dermatitis and food allergies. Allergens include dust, pollen, mold, and pet dander or pet hair.
In one aspect, the invention provides a method for treating a subject suffering from an allergic condition, in particular an atopic allergic condition, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a cathepsin S inhibitor.
In another aspect, the invention provides a method for treating a subject suffering from an IgE-mediated allergic condition, in particular an atopic allergic condition, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a cathepsin S inhibitor.
A third aspect of the invention provides the use, or the use for the manufacture of a medicament, of a cathepsin S inhibitor for treating an allergic condition, more in particular for treating IgE-mediated allergic conditions, still more in particular treating hay fever, asthma, atopic dermatitis or food allergies. The invention also features anti-allergic pharmaceutical compositions comprising as active ingredient an effective amount of a cathepsin S inhibitor, and a pharmaceutically acceptable carrier. The active ingredient can be formulated in any manner suitable for the particular allergic condition, including aerosol, oral and topical formulations and time-release formulations.
The present invention concerns the treatment of an allergic condition with one or more compounds which can be represented by formula (I): 
wherein:
the dashed line adjacent Cxe2x80x94R6 is absent or an sp2 bond;
Y is nitrogen or R20C;
Z is nitrogen or R21C;
T is nitrogen or R2C;
S is nitrogen or R3C;
provided between 0 and 3 of S, T, Y, and Z are nitrogen; and further provided that one of S, T, Y, and Z can be xe2x95x90N+xe2x80x94Oxe2x80x94 where the remaining three are not nitrogen;
R20 is selected from hydrogen, halogen, C1-5 alkoxy, hydroxy, C1-5 alkyl, cyano, nitro, C1-5 haloalkyl, RoRpN, RoRpNCxe2x95x90O, C2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C1-5 alkylene, phenyl, (phenyl)C1-5 alkylene, R14OCxe2x95x90O, R14S, R14SO, and R14SO2;
R21 is selected from hydrogen, halogen, C1-5 alkoxy, hydroxy, C1-5 alkyl, cyano, nitro, C1-5 haloalkyl, RcRdN, RcRdNCxe2x95x90O, C2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C1-5 alkylene, phenyl, (phenyl)C1-5 alkylene, R15OCxe2x95x90O, R15S, R15SO and R15SO2;
R2 is selected from hydrogen, halogen, C1-5 alkoxy, hydroxy, C1-5 alkyl, cyano, nitro, C1-5 haloalkyl, ReRfN, ReRfNCxe2x95x90O, C2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C1-5 alkylene, phenyl, (phenyl)C1-5 alkylene, R16OCxe2x95x90O, R16S, R16SO and R16SO2;
R3 is selected from hydrogen, halogen, C1-5 alkoxy, hydroxy, C1-5 alkyl, cyano, nitro, C1-5 haloalkyl, RgRhN, C2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C1-5 alkylene, phenyl, (phenyl)C1-5 alkylene, R17OCxe2x95x90O, RmRnNCxe2x95x90O, RmRnNSO2, R17SO and R17SO2;
R5 and R6 are independently selected from hydrogen and C1-5 alkyl;
R7 and R8 independently are hydrogen, C1-5 alkyl, C1-5 alkenyl, C1-5 alkoxy, C1-5 alkylthio, halogen, or 4-7 membered carbocyclyl or heterocyclyl; alternatively, R7 and R8 can be taken together to form an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring, which ring may be unsaturated or aromatic; said ring being optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxy, cyano, nitro, amino, R1, RtOxe2x80x94, RtSxe2x80x94, RtO(C1-5 alkylene)-, RtO(Cxe2x95x90O)xe2x80x94, Rt(Cxe2x95x90O)xe2x80x94, Rt(Cxe2x95x90S)xe2x80x94, Rt(Cxe2x95x90O)Oxe2x80x94, RtO(Cxe2x95x90O)(Cxe2x95x90O)xe2x80x94, RtSO2, NHRu(Cxe2x95x90NH)xe2x80x94, NHRuSO2-, and NHRu(Cxe2x95x90O)xe2x80x94;
Rt is C1-6 alkyl, phenyl, benzyl, phenethyl, or C2-5 heterocyclyl, (C1-5 heterocyclyl)C1-6 alkylene, NH2, mono- or di(C1-6 alkyl)Nxe2x80x94, or R49OR50xe2x80x94, wherein R49 is H, C1-5 alkyl, C2-5 alkenyl, phenyl, benzyl, phenethyl, C1-5 heterocyclyl, or (C1-5 heterocyclyl)C1-6 alkylene and R50 is C1-5 alkylene, phenylene, or divalent C1-5 heterocyclyl; and
Ru can be H in addition to the values for Rt;
Rc is hydrogen, C1-5 alkyl, phenyl, C2-5 heterocyclyl, C2-8 acyl, aroyl, R10OCxe2x95x90Oxe2x80x94, RiRjNCxe2x95x90O, R10SOxe2x80x94, R10SO2-; and RiRjNSO2;
Re is hydrogen, C1-5 alkyl, phenyl, C2-5 heterocyclyl, C2-8 acyl, aroyl, R40OCxe2x95x90O, R43R44NCxe2x95x90O, R40SO, R40SO2, and R43R44NSO2-;
Rm is hydrogen, C1-5 alkyl, phenyl, C2-5 heterocyclyl, C2-8 acyl, aroyl, R41OCxe2x95x90O, R45R46NCxe2x95x90O, R41SO2, R45R46NSO2;
Ro is hydrogen, C1-5 alkyl, phenyl, C2-5 heterocyclyl, C2-8 acyl, aroyl, R42OCxe2x95x90O, R47R46NCxe2x95x90O, R42SO, R42SO2, and R47R48NSO2;
each of Rd, Rf, Rn, and Rp is independently selected from hydrogen, C1-5 alkyl, phenyl, and C2-5 heterocyclyl; in addition, Rc and Rd, Re and Rf, Rm and Rn, or Ro and Rp, independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
each of R9, R10, R11, R14, R15, R16, R17, R40, R41, and R42 is independently C1-5 alkyl, phenyl, or C2-5 heterocyclyl;
each of Ri and Rj, Rk and Rl, R43 and R44, R45 and R46, R47 and R48 are independently hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, or C2-5 heterocyclyl; in addition, Ri and Rj, and Rk and Rl, R43 and R44, R45 and R46, and R47 and R48, independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
R9 is hydrogen, C1-5 alkyl, phenyl, or C2-5 heterocyclyl, C2-8 acyl, aroyl,
R9OCxe2x95x90O, R18R19NCxe2x95x90O, R9SO, R9SO2, or R18R19NSO2;
Rh is hydrogen, C1-5 alkyl, phenyl, or C2-5 heterocyclyl; alternatively, R9 and Rh can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
R18 and R19 independently are hydrogen , C1-5 alkyl, phenyl, or C2-5 heterocyclyl; alternatively, R18 and R19 can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
n is 0, or 2;
G is C3-6 alkenediyl or C3-6 alkanediyl, optionally substituted with hydroxy, halogen, C1-5 alkyl, C1-5 alkoxy, oxo, hydroximino, CO2Rk, NRkRl, (L)xe2x80x94C1-4 alkylene-, RkRlNCO2, [(L)xe2x80x94C1-5 alkylene]amino, N3, or (L)xe2x80x94C1-5 alkoxy;
L is amino, mono- or di-C1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, or piperazinyl, wherein available ring nitrogens can be optionally substituted with C1-5 alkyl, benzyl, C2-5 acyl, C1-5 alkylsulfonyl, or C1-5 alkoxycarbonyl;
Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with between 1 and 3 substituents independently selected from halogen, C1-5 alkoxy, C1-5 alkyl, C2-5 alkenyl, cyano, azido, nitro, R22R23N, R22S, R22SO, R22SO2, R22OCxe2x95x90O, R22R23NCxe2x95x90O, C1-5 haloalalkyl, C1-5 haloalkoxy, C1-5 haloalkylthio, and C1-5 alkylthio;
R22 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, benzyl, C2-5 heterocyclyl, C2-8 acyl, aroyl, R11OCxe2x95x90O, R24R25NCxe2x95x90O, R22S, R11SO2, or R24R25NSO2;
R23 is hydrogen, C1-5 alkyl, phenyl, benzyl, or C2-5 heterocyclyl; alternatively, R22 and R23 can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
R24 and R25 are independently hydrogen, C1-5 alkyl, phenyl, benzyl, or C1-5 heteroaryl; alternatively, R24 and R25 can be taken together to form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
R32 is hydrogen, C1-5 alkyl, cyano, C1-5 hydroxyalkyl, C2-8 acyl, xe2x80x94(Cxe2x95x90O)NRvRx, CHO, or C1-6 alkoxycarbonyl, wherein each of Rv and Rx is independently selected from H , C1-5 alkyl, C1-5 hydroxyalkyl, C1-5 heterocyclyl, (C1-5 heterocyclyl) C1-5 alkylene, C1-5 aminoalkylene, C3-8 acyloxy, CHO, C1-6 alkoxycarbonyl, and cyano;
Q is NR33, S, or O;
R33 represents hydrogen, C1-5 alkyl, phenyl, benzyl, phenethyl, C2-5 heterocyclyl, (C2-5 heterocyclyl)C1-5 alkylene, C2-8 acyl, aroyl, R35OCxe2x95x90O, R36R37NCxe2x95x90O, R35SO, R35S, R35SO2 and R36R37NSO2;
R35 is selected from hydrogen, C1-5 alkyl, phenyl, benzyl, phenethyl, and C2-5 heteroaryl;
R36 and R37 are each independently selected from hydrogen, C1-5 alkyl, phenyl, or C2-5 heteroaryl; alternatively, R36 and R37 can be taken together to form an optionally substituted 4- to 7-membered ring heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
wherein each of the above hydrocarbyl or heterocarbyl groups, unless otherwise indicated, and in addition to any specified substituents, is optionally and independently substituted with between 1 and 3 substituents selected from methyl, halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C1-5 alkyl, C1-5 alkoxy, xe2x80x94COOH, C2-6 acyl, [di(C1-4 alkyl)amino]C2-5 alkylene, [di(C1-4 alkyl)amino] C2-5 alkyl-NHxe2x80x94COxe2x80x94, and C1-5 haloalkoxy;
or a pharmaceutically acceptable salt, amide, or ester thereof; or a stereoisomeric form thereof.
The disclosed compounds are high-affinity inhibitors of the proteolytic activity of human cathepsin S. For use in medicine, the preparation of pharmaceutically acceptable salts of compounds of formula (I) may be desirable.
Certain compounds of the present invention may have one stereogenic atom and may exist as two enantiomers. Certain compounds of the present invention may have two or more stereogenic atoms and may further exist as diastereomers. It is to be understood by those skilled in the art that all such stereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Another aspect of the invention provides pharmaceutical anti-allergic compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. A further embodiment of the invention is a process for making an anti-allergic pharmaceutical composition comprising mixing a disclosed compound as described above, with a suitable pharmaceutically acceptable carrier.
The invention also contemplates pharmaceutical compositions comprising more than one compound of formula (I) and compositions comprising a compound of formula (I) and another pharmaceutically active agent.
The invention features a method of treating allergic disorders or conditions mediated by the cathepsin S enzyme, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. If more than one active agent is administered, the therapeutically effective amount may be a jointly effective amount. The compounds described herein inhibit the protease activity of human cathepsin S, an enzyme involved in the immune response. In preferred embodiments, cathepsin S inhibition is selective.
Additional features and advantages of the invention will become apparent from the detailed description below, including examples, and the appended claims.